Protein kinases (PKs) are a family of enzymes, which are involved in a variety of cellular processes, including signal transduction and growth regulation. Protein kinases (PKs) remove the γ-phosphate from ATP and covalently attach it to one of three amino acids that have a free hydroxyl group on substrate proteins. Most kinases act on both serine and threonine, others act on tyrosine, and a number (dual specificity kinases) act on all three. These phosphorylation processes by PKs are key events in cellular signaling.
Receptor tyrosine kinases (RTKs) constitute one class of protein tyrosine kinases (PTKs). These kinases belong to a family of transmembrane proteins and have been implicated in cellular signaling pathways. The predominant biological activity of some receptor kinases is the stimulation of cell growth and proliferation, while other receptor tyrosine kinases are involved in inhibiting growth and promoting differentiation. In some instances, a single tyrosine kinase can inhibit, or stimulate, cell proliferation depending on the cellular environment in which it is expressed (Schlessinger and Ullrich, Neuron (1992), 9(3): 383-391). RTKs include receptors for platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), hepatocyte growth factor (HGF), insulin, insulin-like growth factor 1 (IGF-1), nerve growth factor (NGF), vascular endothelial growth factor (VEGF), macrophage colony stimulating factor (M-CSF) and others.
Receptor tyrosine kinases are mainly composed of an extracellular glycosylated ligand binding domain, a transmembrane domain and a cytoplasmic catalytic domain that can phosphorylate tyrosine residues. Binding of a ligand to membrane-bound receptors induces the formation of receptor dimers and allosteric changes thus activating the intercellular kinase domains which further results self-phosphorylation (autophosphorylation and/or transphosphorylation) of the receptor on tyrosine residues. Receptor phosphorylation stimulates physical association of the activated receptor with target molecules. Some of the target molecules are, in turn, phosphorylated, a process which transmits the signal to the cytoplasm. The secondary signal transducer molecules generated by activated receptors, result in a signal cascade that regulates cell functions such as cell division or differentiation. Intracellular signal transduction is reviewed in Aaronson, Science (1991), 254: 1146-1153; Schlessinger, J. Trends Biochem. Sci. (1988), 13: 443-447; and Ullrich and Schlessinger, Cell (1990), 61: 203-212.
Various cell proliferative disorders have been associated with defects in pathways mediated by PTKs. Enhanced activities of PTKs resulting from overexpression of the normal kinase, upregulation of ligands of receptor tyrosine kinases or activating mutations, are a hallmark of many diseases which involve cellular proliferation, including cancer. Examples of specific receptor tyrosine kinases associated with cell proliferative disorders include platelet derived growth factor receptor (PDGFR), insulin-like growth factor 1 receptor (IGF-1R), epidermal growth factor receptor (EDFR), and the related HER2.
The involvement of PTKs in various diseases renders them as targets for antiproliferative drugs. Numerous PTK blockers have been described in the literature including proposed mechanisms of action (Levitzki et al., Science (1995), 267: 1782-88; and Posner et al., Mol. Pharmacol. (1994), 45: 673-683). A family of PTK inhibitors, named tyrphostins, designed to mimic the tyrosine substrate was disclosed in Levitzki et al., Science (1995), 267: 1782-88; Levitzki et al., Biochem. Pharm. (1990), 40: 913-920; Levitzki et al., FASEB J. (1992), 6: 3275-3282; U.S. Pat. Nos. 5,217,999 and 5,773,476. The pharmacophores of these tyrphostins, and in particular tyrphostins of the benzylidene malonitril type, are the hydrophilic catechol ring and the more lipophilic substituted cyano-vinyl radical. Kinetic studies have shown that some tyrphostin compounds are pure competitive inhibitors vis-à-vis tyrosine substrates whereas for the ATP binding site they act as non-competitive inhibitors (Yaish et al., Science (1988), 242: 933-935; and Gazit et al., J. Med. Chem. (1989), 32: 2344-2352). Nonetheless, many tyrphostins have shown competitive inhibition against both the substrate and ATP binding site (Posner et al., Mol. Pharmacol. (1994), 45: 673-683).
In a related group of tyrphostins, the hydrophilic catechol ring was exchanged by lipophilic dichloro- or dimethoxy-phenyl groups, to yield EGFR kinase inhibitors, effective in the low micromolar range (Yoneda et al., Cancer Res. (1991), 51: 4430-4435). These tyrphostins were further administered to tumor-bearing nude mice together with anti-EGFR monoclonal antibodies at a suboptimal dose to afford markedly enhanced inhibition of tumor growth.
WO 99/24442 discloses compounds for inhibiting intracellular signal transduction mediated by one or more molecular interactions involving a phosphotyrosine-containing protein.
WO 2008/068751 to some of the inventors of the present invention, discloses novel tyrphostins compounds having increased inhibitory properties of insulin-like growth factor 1 receptor (IGF-1R), platelet derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR), and IGF-1R-related insulin receptor (IR) activation and signaling.
WO 2009/147682 to some of the inventors of the present invention, discloses new tyrphostin derivatives acting as protein kinase (PK) and receptor kinase (RK) signaling modulators.